A promising approach to immunotherapy concerns use of antagonistic antibodies against immune checkpoint proteins (e.g., Pardoll, 2012, Nature Reviews Cancer 12:252-64). Immune checkpoints function as endogenous inhibitory pathways for the immune system to maintain self-tolerance and to modulate the duration and extent of immune response to antigenic stimulation (Pardoll, 2012). In their normal function, activity of checkpoint proteins modulates the immune response to prevent development of autoimmune disease (e.g., He et al., 2017, J Autoimmun 79:1-3). However, it appears that tumor tissues may co-opt the checkpoint system to reduce the effectiveness of the host immune response, resulting in tumor growth (see, e.g., Pardoll, 2012, Nature Reviews Cancer 12:252-64; Nirschl & Drake, 2013, Clin Cancer Res 19:4917-24). Checkpoint molecules include CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), LAG-3 (lymphocyte activation gene-3), TIM-3 (T cell immunoglobulin and mucin protein-3) and several others (Pardoll, 2012, Nature Reviews Cancer 12:252-64; Nirschl & Drake, 2013, Clin Cancer Res 19:4917-24).
Antibodies against several of the checkpoint proteins (CTLA-4, PD-1, PD-L1) are in clinical trials and have shown unexpected efficacy against tumors that were resistant to standard treatments. Use in human cancer therapy has been approved by the FDAfor ipilimumab (anti-CTLA-4, Bristol-Myers Squibb) in malignant melanoma (Cameron et al, 2011, Drugs 71:1093-104); pembrolizumab (anti-PD-1, Merck & Co.) in melanoma, head and neck cancer, Hodgkin lymphoma, urothelial cancer, gastric cancer and metastatic NSCLC that expresses PD-1 (Press Release, Merck & Co., dated Sep. 22, 2017, “FDA Approves Merck's KEYTRUDA® for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-1 (CPS Greater Than or Equal to 1)”); nivolumab (anti-PD-1, Bristol-Myers Squibb) in melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer and Hodgkin lymphoma (Larkins et al., 2017, The Oncologist 22:873-78; Kasamon et al., 2017, Oncologist 22:585-91), and five anti-PD-1 antibodies, for example, atezolizumab (anti-PD-L1, Roche) in bladder cancer and metastatic NSCLC (Ning et al., 2017, Oncologist 22:743-49; Weinstock et al., 2017, Clin Cancer Res 23:4534-39).
Studies with checkpoint inhibitor antibodies for cancer therapy have generated unprecedented response rates in cancers previously thought to be resistant to cancer treatment (see, e.g., Ott & Bhardwaj, 2013, Frontiers in Immunology 4:346; Menzies & Long, 2013, Ther Adv Med Oncol 5:278-85; Pardoll, 2012, Nature Reviews 12:252-264; Mavilio & Lugli, 2013, Oncoimmunology 2:e26535). Therapy with antagonistic checkpoint blocking antibodies against CTLA-4, PD-1 and PD-1 is one of the most promising new avenues of immunotherapy for cancer and other diseases. However, a need continues to exist for more effective checkpoint inhibitor antibodies, preferably with the ability to block binding of PD-1 to PD-1.